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Molecular Response to Imatinib and Its Correlation with mRNA Expression Levels of Imatinib Influx Transporter (OCT1)
S Chhikara1, S Sazawal, T Seth
1Department of Hematology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India.
Abstract:
Background and objectives: Imatinib mesylate is approved for the treatment of Chronic Myeloid Leukemia (CML). About 20% of patients with CML do not respond to treatment with Imatinib either initially or because of acquired resistance. In addition to mutated BCR-ABL1 kinase, the organic cation transporter1 (OCT1, encoded by SLC22A1) has been considered to contribute to Imatinib resistance in patients with chronic myeloid leukemia (CML). OCT1 has been reported to be the main influx transporter involved in Imatinib uptake into CML cells. To date, only a few studies have been reported on involvement of influx transporters in development of Imatinib resistance. Therefore this study was aimed to determine the expression level of Imatinib uptake transporter (OCT1) in CML patients and to correlate this level with molecular response. Methods: One hundred fifty eight patients on Imatinib were considered for gene expression analysis study for OCT1 gene. Total RNA was extracted from peripheral blood mononuclear cells. Complementary DNAs (cDNAs) were synthesized and Real Time Polymerase Chain Reaction (RQ-PCR) was performed. Results: High OCT1 expression was present in 81 (51.8%) patients and low OCT1 expression was in 77 (48.7%) patients. Low Sokal risk score group have a significantly high OCT1 expression (p=0.048). The rate of molecular response was higher in those with high OCT1 expression than in those with low OCT1 expression (p=0.05). Both event-free survival and median overall survival were significantly shorter in patients with low OCT1 expressions when compared to the patients with high OCT1 expression (p=0.03 and p=0.05). Conclusions: Our findings demonstrated that the mRNA expression level of OCT1 was significantly correlated with molecular response in CML patients. Based on these findings, present study believes that the pre-therapeutic higher expression of OCT1 may help to predict response to imatinib therapy in CML patients.
Insights
Organic cation transporter 1 (OCT1) expression levels in chronic myeloid leukemia (CML) patients correlate with imatinib treatment response. Higher OCT1 expression predicts better molecular response and survival outcomes in CML patients receiving imatinib therapy.
Area of Science:
- Hematology
- Oncology
- Pharmacogenomics
Background:
- Imatinib mesylate is a standard treatment for Chronic Myeloid Leukemia (CML).
- Approximately 20% of CML patients exhibit primary resistance or develop acquired resistance to imatinib.
- The organic cation transporter 1 (OCT1), encoded by SLC22A1, is implicated in imatinib uptake and resistance.
Purpose of the Study:
- To investigate the expression level of the imatinib uptake transporter OCT1 in CML patients.
- To correlate OCT1 expression levels with the molecular response to imatinib therapy.
- To assess the impact of OCT1 expression on patient survival outcomes.
Main Methods:
- Gene expression analysis of the OCT1 gene in 158 CML patients treated with imatinib.
- RNA extraction from peripheral blood mononuclear cells.
- Complementary DNA synthesis followed by Real-Time Polymerase Chain Reaction (RQ-PCR).
Main Results:
- High OCT1 expression was observed in 51.8% of patients, while low expression was found in 48.7%.
- Higher OCT1 expression was significantly associated with a better molecular response to imatinib (p=0.05).
- Patients with low OCT1 expression had significantly shorter event-free and overall survival (p=0.03 and p=0.05, respectively).
Conclusions:
- The mRNA expression level of OCT1 is significantly correlated with molecular response in CML patients.
- Pre-therapeutic OCT1 expression may serve as a predictive biomarker for imatinib therapy response in CML.
- OCT1 transporter activity is crucial for effective imatinib treatment in CML.
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